Expeditious Construction of (+)-Mintlactone via Intramolecular Hetero-Pauson-Khand Reaction Peng Gao,†,‡ Peng-Fei Xu,† and Hongbin Zhai*,† Key Laboratory of Synthetic Chemistry of Natural Substances and State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China 200032, and State Key Laboratory of Applied Organic Chemistry and Department of Chemistry, Lanzhou UniVersity, Lanzhou, Gansu, China 730000
FIGURE 1. (+)- and (-)-mintlactone and (+)- and (-)-isomintlactone. SCHEME 1.
Synthesis of (+)-Mintlactone (1)
[email protected] ReceiVed January 9, 2009
(+)-Mintlactone, a bicyclic monoterpene natural product, has been efficiently assembled from (-)-citronellol in three steps. The synthesis features nitrous acid-induced formal isopropylidene “demethanation” and the molybdenum-mediated intramolecular hetero-Pauson-Khand reaction.
(+)-Mintlactone (1) and (-)-isomintlactone (2) were isolated as endo R,β-unsaturated monoterpene-γ-lactones from the oil of the woods of Bursera graVeolens by Iwabuchi (Figure 1).1 Their enantiomers, ent-(-)-1 and ent-(+)-2, were isolated for the first time in 1968 from Mentha cardiaca.2 The latter two p-menthanolides are also present both in Mentha arVensis3 and as minor constituents of the commercial essential oil (peppermint oil) of Mentha piperita L.4 Surprisingly, the synthesis of these bicyclic monoterpene natural products has attracted immense attention in the field of synthetic organic chemistry.5-8 For instance, Bates7o recently reported a novel ten-step synthesis of (-)-mintlactone from the THP ether of propargyl alcohol via a highly diastereoselective tin(II) chloride-mediated intramolecular propargylic Barbier reaction followed by an allenol cyclocarbonylation. In addition, starting from citronellal, Shishido and co-workers7g realized a total synthesis of (-)mintlactone in ten steps by employing the fused butenolide †
Shanghai Institute of Organic Chemistry. Lanzhou University. (1) Iwabuchi, H. Abstracts of Papers: 41st Symposium on the Chemistry of Terpenes, Essential Oils, and Aromatics, Morioka, Japan, 1997; p, R1. (2) Muraki, S. Abstracts of Papers: 12th Symposium on the Chemistry of Terpenes, Essential Oils, and Aromatics Shizuoka, Japan, 1968; p 13. (3) Sakata, I.; Hashizume, T. Agric. Biol. Chem. 1971, 35, 128. (4) Takahashi, K.; Someya, T.; Muraki, S.; Yoshida, T. Agric. Biol. Chem. 1980, 44, 1535. (5) For a review, see: Ferraz, H. M. C.; Luiz, S.; Longo, L. S., Jr.; Grazini, M. V. A. Synthesis 2002, 2155. (6) For the synthesis of (+)-mintlactone, see: Crisp, G.; Meyer, A. G. Tetrahedron 1995, 51, 5831. ‡
2592 J. Org. Chem. 2009, 74, 2592–2593
construction strategy based on an intramolecular [3 + 2] cycloaddition of nitrile oxide. Its unique structural features prompted us to develop an original and concise strategy to construct mintlactone. The molybdenum-mediated intramolecular hetero-Pauson-Khand reaction (hetero-PKR) of 1,6- and 1,7-yne aldehydes has been identified as an ultraefficient method for the synthesis of fused γ-butenolides.9 We envisioned that the intramolecular heteroPKR should perfectly serve our initiative in the synthesis of mintlactone. As outlined in Scheme 1, our synthesis commenced from formal “demethanation” of (-)-citronellol (3) with nitrous acid by following Abidi’s protocol.10 Thus alkynol 4 was produced directly in a single step from 3 in a yield (26%) identical with (7) For the synthesis of (-)-mintlactone, see: (a) Foote, C. S.; Wuesthoff, M. T.; Wexler, S.; Schenck, G. O.; Schulte-Elte, K.-H. Tetrahedron 1967, 23, 2583. (b) Hirsch, J. A.; Eastman, R. H. J. Org. Chem. 1967, 32, 2915. (c) Tadwalkar, V. R.; Rao, A. S Indian J. Chem. 1971, 9, 1416. (d) Takahashi, K.; Someya, T.; Muraki, S.; Yoshida, T. Agric. Biol. Chem. 1980, 44, 1535. (e) Akhila, A.; Srivastava, R.; Rani, K.; Thakur, R. S. Phytochemistry 1991, 30, 485. (f) Carda, M.; Marco, J. A. Tetrahedron Lett. 1991, 32, 5191. (g) Shishido, K.; Irie, O.; Shibuya, M. Tetrahedron Lett. 1992, 33, 4589. (h) Carda, M.; Marco, J. A. Tetrahedron 1992, 48, 9789. (i) Chavanp, S. P.; Zubaidha, P. K.; Dhondge, V. D. Tetrahedron 1993, 49, 6429. (j) Lohray, B. B.; Nandana, E.; Bhushan, V. Indian J. Chem., Sect. B 1997, 36, 226. (k) Shimizu, M.; Kamikubo, T.; Ogasawara, K. Synlett 1998, 655. (l) Ferraz, H. M. C.; Grazini, M. V. A.; Ribeiro, C. M. R.; Brocksom, U.; Brocksom, T. J. J. Org. Chem. 2000, 65, 2606. (m) Curini, M.; Epifano, F.; Marcotullio, M. C.; Montanari, F. Synlett 2004, 368. (n) Pandey, R. K.; Upadhyay, R. K.; Shinde, S. S.; Kumar, P. Synth. Commun. 2004, 34, 2323. (o) Bates, R. W.; Sridhar, S. J. Org. Chem. 2008, 73, 8104. (8) For the synthesis of rac-mintlactone, see: (a) Camps, F.; Castells, J.; Pascual, J. J. Org. Chem. 1966, 31, 3510. (b) Camps, F. J. Org. Chem. 1968, 33, 2466. (c) Tsuboi, S.; Shimozuma, K.; Takeda, A. J. Org. Chem. 1980, 45, 1517. (d) Kitagawa, I.; Tsujii, S.; Nishikawa, F.; Shibuya, H. Chem. Pharm. Bull. 1983, 31, 2639. (e) Fujita, T.; Watanabe, S.; Nishikawa, F.; Itoh, K.; Sugahara, K. J. Chem. Technol. Biotechnol. 1985, 35A, 57. (f) Cory, R. M.; Ritchie, B. M.; Shrier, A. M. Tetrahedron Lett. 1990, 31, 6789. (g) Chavan, S. P.; Zubaidha, P. K.; Ayyangar, N. R. Tetrahedron Lett. 1992, 33, 4605. (h) Tanyeli, C.; Cahskan, Z.; Demir, A. S. Synth. Commun. 1997, 27, 3471. (i) Ferraz, H. M. C.; Grazini, M. V. A.; Silva, L. F., Jr.; Longo, L. S. Synth. Commun. 1999, 29, 1953. (j) Chavan, S. P.; Govande, C. A. Green Chem. 2002, 4, 194. (k) Tanabe, Y.; Mitarai, K.; Higashi, T.; Misaki, T.; Nishii, Y. Chem. Commun. 2002, 2542.
10.1021/jo900045k CCC: $40.75 2009 American Chemical Society Published on Web 02/19/2009
SCHEME 2.
Conformational Analysis for the Hetero-PKR
and the Mo(CO)3(DMF)3-mediated intramolecular hetero-Pauson-Khand reaction. Experimental Section
that obtained from the racemic citronellol by Kraft and Berthold,11 who failed to reproduce the reported 95% yield of Abidi for the same transformation.10a After treatment with PCC in dichloromethane at room temperature for 2 h, alcohol 4 was smoothly converted to ynal 5 in 68% yield. Even though 5 was reportedly preparable in one step (via formal “demethanation”) from citronellal in moderate yield (70%),10a it remained irreproducible in our hand. Since the 1,6-yne aldehyde 5 was not very stable in air at room temperature, it should be used in the next step immediately. Exposure9 of the ynal to the freshly prepared organomolybdenum catalyst, Mo(CO)3(DMF)3,12 in tetrahydrofuran at room temperature for 1 h led to (+)-mintlactone (1, 39%) along with its inseparable diastereomer, presumably (-)isomintlactone (2, 3%), in an optimized combined yield of 42% {[R]18D +54.4 (c 0.95, CHCl3); lit.7n (-)-mintlactone [R]25D -57 (c 2, CHCl3); lit.7o (-)-mintlactone [R]24D -59.2 (c 2.4, CHCl3)}. One stereogenic center, two rings, and three covalent bonds (1 C-O and 2 C-C) were formed in this remarkable intramolecular hetero-PKR, which proceeded in high diastereoselectivity (C-3, dr ) 12:1) according to the line integrals of the 1H NMR spectrum. The diastereoselectivity observed in the hetero-PKR can be explained by a conformational analysis (Scheme 2). Because a chair conformation (TS-1) for a simplified transition state structure theoretically has lower energy than a twist boat one (TS-2), (+)-mintlactone (1) should emerge as a major product. In summary, we have accomplished a three-step assembly of (+)-mintlactone (despite the relatively low yields for the first and third steps), which may somehow be used as an example to illustrate the significance of the concepts of “step economy”13 and “strategic efficiency”.14 Key features of the current synthesis include HNO2-induced formal isopropylidene “demethanation” (9) Adrio, J.; Carretero, J. C. J. Am. Chem. Soc. 2007, 129, 778. (10) (a) Abidi, S. L. Tetrahedron Lett. 1986, 27, 267. (b) Abidi, S. L. J. Org. Chem. 1986, 51, 2687. (c) Abidi, S. L. J. Chem. Soc., Chem. Commun. 1985, 1222. For mechanistic studies on nitrous acid-induced conversion of an isopropylidene group into an alkyne, see: (d) Corey, E. J.; Seibel, W. L; Kappos, J. C. Tetrahedron Lett. 1987, 28, 4921. (e) Boivin, J.; Pillot, E.; Williams, A.; Roger, W.; Zard, S. Z. Tetrahedron Lett. 1995, 36, 3333. (11) Kraft, P.; Berthold, C. Synthesis 2008, 543. (12) For the preparation of Mo(CO)3(DMF)3, see the Supporting Information. See also: Pascuali, M.; Leoni, P.; Sabatino, P.; Braga, D. Gazz. Chim. Ital. 1992, 122, 275. (13) Wender, P. A.; Miller, B. L. In Organic Synthesis: Theory and Applications; Hudlicky, T., Ed.; JAI Press: Greenwich, CT, 1993; Vol. 2, p 27. (14) Qiu, F. Can. J. Chem. 2008, 86, 903.
Compound 4. NaNO2 (25.0 g, 362 mmol) was added portionwise to a vigorously stirred solution of (-)-citronellol (2.10 g, 13.4 mmol) in HOAc-H2O (5:2, 63 mL) at 0 °C and a large amount of gas (NOx) and lather was produced. After the reaction mixture was stirred at 0 °C for 1 h, the cooling bath was removed and stirring continued at rt for 24 h. The reaction mixture was heated at 54 °C for 24 h and then at rt for 24 h before being poured into H2O (140 mL) and extracted with CH2Cl2 (3 × 50 mL). The combined organic extracts were washed successively with H2O (50 mL) and brine (50 mL), dried (Na2SO4), and concentrated under reduced pressure. Chromatography (petroleum ether (30-60 °C)/Et2O, 4:1) provided compound 4 (498 mg, 26%) as a light yellow oil: [R]20D -4.21 (c 2.0, CHCl3); 1H NMR (CDCl3, 300 MHz) δ 0.89 (d, J ) 6.0 Hz, 3H), 1.23-1.42 (m, 2H), 1.48-1.68 (m, 4H), 1.76 (s, 3H), 2.11-2.25 (m, 2H), 3.60-3.76 (m, 2H). Compound 5. To a solution of compound 5 (193 mg, 1.38 mmol) in CH2Cl2 (40 mL) were added PCC (297 mg, 1.38 mmol) and Celite (1.40 g). The reaction mixture was stirred under argon for 2 h, filtered, and concentrated to give a residue, which was quickly chromatographed (petroleum ether (30-60 °C)/Et2O, 20:1) to afford compound 5 (129 mg, 68%) as a colorless oil: [R]21D -18.4 (c 1.9, CH2Cl2); 1H NMR (CDCl3, 300 MHz) δ 0.97 (d, J ) 6.0 Hz, 3H), 1.37-1.54 (m, 2H), 1.77 (t, J ) 2.4 Hz, 3H), 2.13-2.28 (m, 4H), 2.38-2.45 (m, 1H), 9.76 (s, 1H); 13C NMR (CDCl3, 75 MHz) δ 3.4, 16.3, 19.4, 27.2, 35.8, 50.5, 75.9, 78.4, 202.8; MS (EI) 138 (M+, 2), 123 (44), 109 (41), 79 (100), 67 (87), 41 (97). HRMS (EI) calcd for C9H14O 138.1045, found 138.1046. Compound 1. A Schlenk flask was charged under argon with freshly prepared Mo(CO)3(DMF)3 (180 mg, 0.45 mmol), capped with a rubber septum, and evacuated and backfilled with argon twice. A solution of freshly prepared yne-aldehyde 6 (62 mg, 0.45 mmol) in THF (10 mL) was added via syringe. The reaction mixture was stirred at rt for 1 h and the crude reaction mixture was filtered through a plug of Celite with the aid of CH2Cl2.The solvents were evaporated to give a residue, which was purified by chromatography (petroleum ether (30-60 °C)/EtOAc, 20:1) to afford an inseparable mixture (31 mg, 42%, dr ) 12:1) of (+)-mintlactone (1, 39%) and (-)-isomintlactone (2, 3%) as a colorless oil: [R]18D +54.4 (c 0.95, CHCl3); 1H NMR (CDCl3, 400 MHz) δ 0.99 (d, J ) 6.8 Hz, 3H), 0.86-1.04 (m, 2H), 1.62-1.76 (m, 1H), 1.78 (t, J ) 1.6 Hz, 3H), 1.85-1.95 (m, 1H), 2.17 (td, J ) 14.0, 5.6 Hz, 1H), 2.35-2.43 (m, 1H), 2.77 (ddd, J ) 14.0, 4.4, 2.0 Hz, 1H), 4.60 (dd, J ) 11.2, 6.0 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ 8.1, 21.2, 25.4, 29.7, 34.5, 41.9, 79.9, 119.5, 162.3, 174.8; MS (EI) 166 (M+, 9), 137 (6), 65 (100); HRMS (EI) calcd for C10H14O2 166.0994, found 166.0996.
Acknowledgment. Financial support was provided by grants from NSFC (90713007; 20772141; 20625204; 20632030) and MOST_863 (2006AA09Z405; 2006AA09Z446). Supporting Information Available: The Experimental procedures and copies of 1H and 13C NMR spectra for all new compounds. This material is available free of charge via the Internet at http://pubs.acs.org. JO900045K
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